Glutamate MRS During Ketamine Infusion

Aims:

This feasibility study aims to better understand the neurobiology of major depression and how
ketamine may therapeutically impact brain function. This research may provide important
insights into the mechanism of ketamine response, thus, potentially increasing the likelihood
of successful treatment interventions and decrease the number of ineffective treatments
and/or risk for serious side effects.

SPECIFIC AIMS:

Primary aim: Evaluate change in central glutamate (i.e. MR spectroscopic CSF corrected
glutamate in ACC) and peripheral glutamate (i.e. high-performance liquid chromatography
[HPLC] measured glutamate) after a single 40-minute infusion of i.v. racemic ketamine, and
change in symptoms of depression measured using MADRS scale in patients with
treatment-resistant major depression (baseline to 24 hours) (n=10).

Inclusion:

- Ability to provide informed consent;

- Current psychiatric inpatient (voluntary only) or outpatient treatment;

- Male or female;

- Age 18-65 years;

- Meets clinical DSM-5 diagnostic criteria for major depressive disorder;

- PHQ-9 total score ≥ 15 at screening and at baseline (just prior to first acute phase
ketamine infusion);

- Treatment-resistant depression, as defined by failure of at least two previous
antidepressant treatments within the current depressive episode. Failed antidepressant
treatments can include pharmacotherapy for depression at an adequate dose for at least
8 weeks, or an acute series of at least 6 administrations of electroconvulsive therapy
(ECT);

- Ability to pass a comprehension assessment test related to effects of ketamine and
trial objectives and criteria.

Exclusion:

- Inability to speak English

- Any current psychiatric diagnosis other than anxiety disorders needing concurrent
antidepressant therapy

- Personality disorder being the primary diagnosis

- Diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder, post-traumatic
stress disorder, or active psychotic symptoms;

- Ongoing prescription of > 4 mg lorazepam equivalents (total) daily, or morning dosing
of any benzodiazepine at the time of assessment;

- On current medications known to affect glutamate (i.e., Riluzole, Carbamazepine) or
GABA (zaleplon, zolpidem, zopiclone, Valproate, Gabapentin, Pregabalin, tiagabine, and
vigabatrin)

- Currently undergoing transcranial magnetic stimulation, vagal nerve stimulation, or
deep brain stimulation as either an acute or maintenance treatment of depression;

- ECT in the past 12 months;

- Any active or unstable medical condition judged by the study psychiatrist as
conferring too great a level of medical risk to allow inclusion in the study;

- Use or abuse of methamphetamine, cocaine, cannabis, or stimulants (prescribed and
illicit) within the past 12 months;

- Any current substance use disorder (excluding nicotine and caffeine). Note: Persons
will be allowed to enroll in this study if their substance use is in complete (not
partial) and sustained (> 1 year) remission;

- History of traumatic brain injury that resulted in loss of consciousness;

- Developmental delay, intellectual disability, or intellectual disorder;

- Clinical or self-reported diagnosis of delirium, encephalopathy, or related clinical
diagnosis within the prior 12 months;

- Cognitive disorder (mild and major categories, per DSM-);

- Received ketamine treatment for depression within the prior 2 months;

- History of either poor antidepressive response to or poor tolerability of ketamine
(any route of administration) when previously administered for treating symptoms of
depression;

- History of hypothyroidism unless taking a stable dose of thyroid medication and
asymptomatic for 6 months;

- Hepatic insufficiency (2.5 X ULN for AST or ALT) within 1 year of consent, past liver
transplant recipient, and/or clinical diagnosis of cirrhosis of the liver;

- Gastroesophageal reflux disease

- Pregnancy, or nursing;

- History of claustrophobia

- Any contraindication to MRI safety questionnaire